STRUCTURE AND MECHANISM OF DNA INTERSTRAND CROSSLINKING

DNA链间交联的结构和机制

• 批准号: 3305244
• 负责人: PAUL B HOPKINS
• 金额: $ 7.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3305244
• 关键词: DNA damage; SDS polyacrylamide gel electrophoresis; alkylating agents; analog; antineoplastic antibiotics; antineoplastics; chemical conjugate; covalent bond; crosslink; drug design /synthesis /production; hydrolysis; intermolecular interaction; mechlorethamine; mitomycin C; nitrogen mustard; nucleic acid sequence; nucleic acid structure; oligonucleotides; pyrroles

Research is proposed in the area of nucleic acid chemistry. Covalent reactions of DNA interstrand crosslinking agents will be investigated. The chemical structures of two interstrand crosslinks, those of a nitrogen mustard and of a highly simplified analog of reductively activated mitomycin C, will be determined at atomic resolution by hydrolysis of structurally homogeneous, interstrand crosslinked DNA fragments containing these crosslinks. The structures of the resulting conjugates will be identified by comparison to authentic, synthetic samples of the expected conjugates. The mechanism by which mitomycin analogs preferentially crosslink 5'-CG sequences in DNA will be investigated using rationally designed synthetic analogs, the interstrand crosslinking sequence preferences of which will be determined at nucleotide resolution. Bifunctional alkylating agents expected on mechanistic grounds to preferentially crosslink the base sequence 5'-GC will be synthesized and studied. DNA interstrand crosslinking agents capable of recognizing and crosslinking a six base pair sequence of DNA will be designed and evaluated.

提议在核酸化学领域进行研究。 共价键 DNA链间交联剂的反应将被研究。 两个链间交联的化学结构， 氮芥和高度简化的还原类似物 活化的丝裂霉素 C，将通过以下方式以原子分辨率测定 结构均质、链间交联 DNA 的水解 含有这些交联的片段。 所得结构 缀合物将通过与真实的、合成的比较来识别 预期缀合物的样品。 丝裂霉素的作用机制 类似物优先交联 DNA 中的 5'-CG 序列 使用合理设计的合成类似物进行研究，链间 其交联顺序偏好将在 核苷酸分辨率。 双功能烷化剂预计 优先交联碱基序列 5'-GC 的机制依据 将被合成和研究。 DNA链间交联剂 能够识别和交联 DNA 的六碱基对序列 将进行设计和评估。